The accumulation of toxic lipids in non-adipose tissues, termed lipotoxicity, is a major means by which obesity produces disease. One therapeutic approach to obesity-related disease, including type 2 diabetes, is to expand the ability of adipose tissues to mobilize and burn fatty acids in situ and thereby prevent lipotoxic lipid accumulation elsewhere. Preclinical experience with ?3-adrenergic agonists and lipase overexpression in adipose tissue indicates that activation of adipocyte lipolysis is sufficient to increase energy expenditure which reduces obesity and improves systemic metabolism. Recent discoveries suggested that adipocyte lipolysis and fat oxidation might be stimulated by agents that release ABHD5 from perilipin1 (PLIN1), and such compounds might be developed for treatment of obesity-related disorders. Screening of the NIH 360,000 compound library identified five such compounds, representing three distinct chemical scaffolds. Initial structure-activity relations experiments demonstrate that the chemical scaffolds are mechanism-based and amenable to chemical improvement. The overall goal of this project is to provide early stage pharmacological validation of the ABHD5/PLIN1 interaction as a therapeutic target for treatment of obesity and obesity-related disease.